Immunophilins are proteins that bind immunosuppressive drugs such as FK506, rapamycin, and cyclosporin A (Schreiber, S. L. (1991) Science 251, 283-287, which is incorporated herein by reference). Immunophilins that bind FK506 or rapamycin are known as FK binding proteins or FKBPs, and those that bind cyclosporin A are known as cyclophilins. Both FK506 and rapamycin are potent immunosuppressants that act by blocking specific intermediate steps in the signal transduction pathways that lead to T-cell activation (Schreiber, S. L. (1992) Cell 70, 365-368, Schreiber, S. L., and Crabtree, G. R. (1992) Immunol. Today 13, 136-142, Liu. J., et al. (1991) Cell 66, 807-815, and Sigal, N. H., and Dumont. F. J. (1992) Annu. Rev. Immunol. 10, 519-560, which are incorporated herein by reference). In T-lymphocytes, binding of FK506 to the well characterized FKBP12 results in the formation of a protein complex of FKBP12 and calcineurin leading to inactivation of calcineurin phosphatase activity (Liu, J., et al. (1992) Biochemistry, 31, 3896-3901, which is incorporated herein by reference) and subsequently inhibition of T-cell activation. Immunophilins also mediate the effects of immunosuppressive drugs in many cell types. For example, FK506 affects signal transduction in B lymphocytes and mast cells, whereas rapamycin inhibits proliferation of yeasts (Koltin, Y., et al. (1991) Mol. Cell. Biol. 11, 1718-1723 and Heitman, J., et al. (1991) Science 253, 905-909 which are incorporated herein by reference). Aside from the ability to interact with immunosuppressive drugs, the relevant physiological function and the endogenous ligands or regulators of immunophilins are not yet known. Because immunophilins are conserved in evolution and all known immunophilins possess peptidylprolyl isomerase or rotamase activity, it has been suggested that they may catalyze protein folding and trafficking in vivo and assembly of protein complexes (Gething, M. J., and Sambrook, J. (1992) Nature 355, 33-45 which is incorporated herein by reference). The Drosophila immunophilin ninaA has been shown to be essential for trafficking of one isoform of rhodopsin to the membrane in the retina (Stamnes, M. A., et al. (1991) Cell 65, 219-227 which is incorporated herein by reference) . The newly discovered immunophilin FKBP52 is part of the glucocorticoid receptor (GR) complex (Tai, P. K., et al. (1992) Science, 256, 1315-1318 which is incorporated herein by reference) and other uncharacterized protein complexes (Tai, P. K., et al. (1993) Biochemistry 32, 8842-8847 which is incorporated herein by reference).
There is a need to identify immunophilin. There is a need to identify compounds that bind to immunophilins. There is a need to study and understand the mechanisms by which immunosuppressive drugs function and for reagents useful in such studies. There remains a need to identify new immunosuppressive drugs. There is a need for kits and methods of identifying such compounds. There is a need for isolated immunophilins, and for compositions and methods of producing and isolating immunophilins. There is a need to isolated proteins that are immunophilins. There is a need to isolated nucleic acid molecules that encode immunophilins.